Myocardial ischemia is a common clinical pathology that occurs in the setting of angina pectoris, acute myocardial infarction, or during cardiac surgery. Myocardial ischemia is a major clinical problem, with its complications being the major cause of mortality and morbidity in Western society.
It has been reported that stimulating glucose oxidation both during and following ischemia can benefit the ischemic heart. Br J Pharmacol 128: 197-205, 1999, Am J Physiol 275: H1533-41, 1998. Biochimica et Biophysica Acta 1225: 191-9, 1994, Pediatric Research 34: 735-41, 1993, Journal of Biological Chemistry 270: 17513-20, 1995. Biochimica et Biophysica Acta 1301: 67-75, 1996, Am J Cardiol 80: 11A-16A, 1997, Molecular & Cellular Biochemistry 88: 175-9, 1989, Circ Res 65: 378-87, 1989, Circ Res 66: 546-53, 1990, American Journal of Physiology 259: H1079-85, 1990, American Journal of Physiology 261: H1053-9, 1991, Am J Physiol Heart Circ Physiol 280: H1762-9, 2001, J Am Coll Cardiol 36: 1378-85, 2000.
To meet the high energy demands of the contracting muscle, the heart must produce a constant and plentiful supply of the free energy carrier, adenosine triphosphate (ATP). This energy is produced by the metabolism of a variety of carbon substrates, including carbohydrates such as glucose. The metabolism of fatty acid is the other major source of energy for the heart.
Glucose metabolism in the heart consists of two important pathways, namely glycolysis and glucose oxidation.
It has been shown that during ischemia (such as that produced by angina pectoris, myocardial infarction or heart surgery) the levels of circulating fatty acids in the plasma can be dramatically elevated. Am Heart J 128: 61-7, 1994. As a result, during ischemia and reperfusion the heart is exposed to high levels of fatty acids, which results in the preferential use of fatty acids as an oxidative substrate over glucose. It further has been reported that this over-reliance on fatty acids as a major source of ATP contributes to fatty acid-induced ischemic damage. This observation has sparked numerous approaches directed at switching substrate utilization back to glucose in an attempt to protect the heart from fatty acid-induced ischemic damage. J Cardiovasc Pharmacol 31: 336-44, 1998, Am Heart J 134: 841-55, 1997, Am Physiol 273: H2170-7, 1997, Cardiovasc Drugs Ther 14: 615-23, 2000, Cardiovasc Res 39: 381-92, 1998, Am Heart J 139: S115-9, 2000, Coron Artery Dis 12: S8-11, 2001, Am J Cardiol 82: 14K-17K., 1998, Molecular & Cellular Biochemistry 172: 137-47, 1997, Circulation 95: 313-5, 1997, Gen Pharmacol 30: 639-45, 1998, Am J Cardiol 82: 42K-49K., 1998, Coron Artery Dis 12: S29-33, 2001, Coron Artery Dis 12: S3-7, 2001, J Nucl Med 38: 1515-21, 1997. Current approaches that are used to manipulate myocardial energy metabolism involve either stimulating glucose metabolism directly or indirectly (i.e., inhibiting fatty acid metabolism).
Since high fatty acid oxidation rates markedly decrease glucose oxidation, one approach to increasing glucose oxidation is to inhibit fatty acid oxidation. This has proven effective both during and following ischemia, and this pharmacological approach is starting to see clinical use. Although a number of pharmacological agents designed to inhibit fatty acid oxidation have recently been developed, the direct β-oxidation inhibitor, trimetazidine, was the first anti-anginal agent widely used that has a mechanism of action that can be attributed to an optimization of energy metabolism Circulation Research. 86: 580-8, 2000.
Trimetazidine is reported to primarily act by inhibiting fatty acid oxidation, thereby stimulating glucose oxidation in the heart.
A second clinically effective agent that is reported to switch energy metabolism from fatty acid to glucose oxidation is ranolazine. It has been reported that this agent stimulates glucose oxidation secondary to an inhibition of fatty acid oxidation Circulation 93: 135-42, 1996.
The detrimental effects of fatty acids on mechanical function during and following ischemia may also be attenuated by agents that increase glucose oxidation directly. Numerous experimental studies have reported that stimulation of glucose oxidation by using dichloroacetate (DCA) following ischemia (at the expense of fatty acids) can benefit the ischemic heart. Am Heart J 134: 841-55, 1997. Although DCA is an effective compound designed to stimulate glucose oxidation, it has a short biological half-life.
Therefore, there is need to develop novel class of compounds and to identify compounds that can stimulate glucose oxidation, have long biological life, and be effective in treatment or prevention of myocardial ischemia